Innate immunity. A Spaetzle-like role for nerve growth factor β in vertebrate immunity to Staphylococcus aureus.
Hepburn L., Prajsnar TK., Klapholz C., Moreno P., Loynes CA., Ogryzko NV., Ogryzko NV., Brown K., Schiebler M., Hegyi K., Antrobus R., Hammond KL., Connolly J., Ochoa B., Bryant C., Otto M., Surewaard B., Seneviratne SL., Grogono DM., Cachat J., Ny T., Kaser A., Török ME., Peacock SJ., Holden M., Blundell T., Wang L., Ligoxygakis P., Minichiello L., Woods CG., Foster SJ., Renshaw SA., Floto RA.
Many key components of innate immunity to infection are shared between Drosophila and humans. However, the fly Toll ligand Spaetzle is not thought to have a vertebrate equivalent. We have found that the structurally related cystine-knot protein, nerve growth factor β (NGFβ), plays an unexpected Spaetzle-like role in immunity to Staphylococcus aureus infection in chordates. Deleterious mutations of either human NGFβ or its high-affinity receptor tropomyosin-related kinase receptor A (TRKA) were associated with severe S. aureus infections. NGFβ was released by macrophages in response to S. aureus exoproteins through activation of the NOD-like receptors NLRP3 and NLRP4 and enhanced phagocytosis and superoxide-dependent killing, stimulated proinflammatory cytokine production, and promoted calcium-dependent neutrophil recruitment. TrkA knockdown in zebrafish increased susceptibility to S. aureus infection, confirming an evolutionarily conserved role for NGFβ-TRKA signaling in pathogen-specific host immunity.